Zenith Epigenetics Advanced Epigenetic Technology November, 2018

Transcription

1 Zenith Epigenetics Advanced Epigenetic Technology November, 2018

2 Forward Looking Statement Safe Harbor Statement. This presentation contains forward-looking statements that involve risks and uncertainties, which may cause actual results to differ materially from the statements made. For this purpose, any statements that are contained herein that are not statements of historical fact may be deemed to be forward- looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of Without limiting the foregoing, the words "believes," "anticipates," "plans," "intends," "will," "should," "expects," "projects," and similar expressions are intended to identify forwardlooking statements. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause actual results, future circumstances, or events to differ materially from those projected in the forward-looking statements. These risks include, but are not limited to, those associated with the success of research and development programs, the regulatory approval process, competition, securing and maintaining corporate alliances, market acceptance of the Company's products, the availability of government and insurance reimbursements for the Company's products, the strength of intellectual property, financing capability, the potential dilutive effects of any financing, reliance on subcontractors and key personnel. The forwardlooking statements are made as of the date hereof, and the Company disclaims any intention and has no obligation or responsibility, except as required by law, to update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise. CONTACT: Donald J. McCaffrey Chairman, President & CEO Suite 300, 4820 Richard Road S.W. Calgary, AB, Canada T3E 6L1 Tel: (403) , Fax:(403) , 2

3 Corporate Profile and Milestones Cash Raised US$1.00 & US$2.00 per unit based on pre-clinical results Founded June 2013 Spin out from Resverlogix Corp. June 2016 Dosing first mcrpc patient with ZEN-3694 Enterprise Value est. US$325MM (US$2.50/Share) est Dec 2016 Initiating combination study with Enzalutamide in MCRPC patients June 2017 Announce issuance of US patent for ZEN-3694 Shares Outstanding 129.6MM 142.0MM fully diluted 2017 Oct 2017 Successful completion of single agent study with ZEN Cash Burn Current US$2MM per quarter 2018 Nov 2018 Successful publications and 80 patients dosed with ZEN

4 Todays Agenda for Zenith Capital Corp. Epigenetics The Mechanism Behind Our Approach The Potential of BET Inhibition Prostate Cancer Rationale Review Promising Early Clinical Results & Case studies Next Steps for Zenith 4

5 Epigenetics - The Mechanism Behind Our Approach The epigenetic code refers to modifications to chromatin components that regulate its activity Turning genes on or off is regulated by these modifications BET (Bromodomain and Extraterminal Domain) proteins recognize these modifications and turn genes on/off 5

6 BET Inhibitors Target Resistance Mechanisms Sensitizing the Tumor to Existing Therapy Adopted from Clinical Cancer Research 2017, 23(7), Many of the escape resistance mechanisms to standard of care treatments involve BRD4 BETi blocks BDR4 binding, resulting in inhibition of tumor oncogenes by disruption of super-enhancers Resistance to several standard of care treatments does not impede sensitivity to BETi, allowing for valuable combination therapy 6

7 Combination Therapy: The Potential of BET Inhibition and ZEN-3694 BET inhibitors has the ability to work synergistically with other therapies overcoming resistance and enhancing the response to the combination, resulting in broader and extended use of existing therapies Hormone-Modulaton Androgen (CRPC) Estrogen (breast cancer). DNA Repair PARPi (Breast, Ovarian, CRPC) BRD4 Kinase-Signaling PI3K (breast, CRPC) RAF (melanoma) Cancers Ecape Mechanism Immuno-Oncology Checkpoint Inhibitors (melanoma, NSCLC, bladder, H&N etc.) The use of BETi is applicable to a number of cancers and therapies ZEN-3694 synergizes with several standard of care cancer drugs 7

8 Zenith s BETi program is Clinically Differentiated Other Clinical BETi Zenith s BETi (ZEN-3694) Significant initial excitement with BETi Poor compounds (benzodiazepine derivatives) and suboptimal single agent clinical strategy in all comer trials led to lack of proof of concept The BETi field now pushing ahead with combination trials in focused clinical trials (BMS, Roche, GSK, Abbvie, BI etc.) 8

9 Todays Agenda for Zenith Capital Corp. Epigenetics The Mechanism Behind Our Approach The Potential of BET Inhibition Prostate Cancer Rationale Review Promising Early Clinical Results & Case studies Next Steps for Zenith 9

10 Revenue The Potential of BET Inhibition & ZEN-3694 Hormone-Modulaton Androgen (CRPC) Estrogen (breast cancer) DNA Repair PARPi (Breast, Ovarian, CRPC) BRD4 Kinase-Signaling PI3K (breast, CRPC) RAF (melanoma) Increase IP life Current multi $B Markets AR antagonists (lead program) PD-1/PD-L1Mabs CDK 4/6 inh. PARPi Immuno-Oncology Checkpoint Inhibitors (melanoma, NSCLC, etc.) Increase duration of therapy Increase patient pool (responders) Differentiation Combination with ZEN-3694 (BETi) 10

11 Todays Agenda for Zenith Capital Corp. Epigenetics The Mechanism Behind Our Approach The Potential of BET Inhibition Prostate Cancer Rationale Review Promising Early Clinical Results & Case studies Next Steps for Zenith 11

12 ZEN-3694 Potential in Patients Developing mcrpc Resistance to Enzalutamide % proliferation compared to DMSO-treated control ZEN-3694 works down stream of current therapies ZEN-3694 works where resistance to existing lead drugs, like Enzalutamide, has evolved The combination of ZEN-3694 and enzalutamide shows strong synergy and is expected to reduce the development of resistance Cell Viability in VCAP P nm R1881 Treated with various concentrations of ZEN with Enzalutamide (3 Day) concentration (um) 3694 Enzalutamide um 3694 Enzalutamide Enzalutamide + 1 um 3694 Enzalutamide + 10 um

13 Todays Agenda for Zenith Capital Corp. Epigenetics The Mechanism Behind Our Approach The Potential of BET Inhibition Prostate Cancer Rationale Review Promising Early Clinical Results & Case studies Next Steps for Zenith 13

14 Zenith s Principal Investigators Eric Small, MD Chief, Dept. of Medicine Rahul Aggarwal, MD Developmental Therapeutics Specialist, Genitourinary Oncologist Howard Scher, MD Chief, Genitourinary Oncology Wassim Abida, MD, PhD Medical Oncologist Joshi Alumkal, MD Associate Professor Allan Pantuck, MD Professor, Dept. of Urology Elizabeth Heath, MD Professor, Dept. Hematology/Oncology Michael Schweizer, MD Oncologist Name Institution Comments David M. Nanus, MD Chief, Division of Hematology and Medical Oncology University of California, San Francisco (UCSF) Memorial Sloane Kettering Cancer Center (MSKCC) Oregon Health Sciences University (OHSU) University of California Los Angeles (UCLA) Karmanos (Wayne State) University of Washington Fred Hutchinson Cancer Center Weill Cornell Medicine Developed abiraterone - #2 CRPC drug, owned by J&J. Developed enzalutamide - #1 CRPC drug, now owned by Pfizer. Developing ARN-509 for J&J Expert in epigenetics in prostate cancer research Involved in enzalutamide and provenge development Genitourinary oncology specialist Experience with AR antagonists Genitourinary oncology specialist 14

15 ZEN-3694 Development in mcrpc: Single Agent Study Results Single agent study key to understanding drug characteristics and supporting combination study H 2H 1H 2H Single agent dose escalation; enzalutamide and/or abiraterone failures N~12 Single agent expansion at RP2D; same population as dose escalation N=12 Key Learnings Maximum tolerated dose (MTD) defined Dose proportional PK Good safety profile, prolonged dosing without dose interruption/reduction is feasible Target modulation shown at doses below MTD Some single agent anti-tumor activity/disease stabilization observed in multiple patients 15

16 Patient X: Prolonged Disease Stabilization Patient Profile: Prior Therapy for mcrpc Provenge Enzalutamide: 6/5/2014 5/5/2016 acquired resistance Abiraterone: 5/22/2016 8/12/2016 primary resistance Study Entry The prognosis for a patient with this profile is typically very poor and the patient would often be offered chemotherapy as the next option. ZEN-3694: 8/24/2016 7/16/2016 (45 weeks) with stable mediastinal nodes over 8 months 32 Weeks 16

17 ZEN-3694 Development in mcrpc: Combination with Enzalutamide H 2H 1H 2H 1H Combination dose escalation ZEN enzalutamide; Patients progressing on abiraterone or enzalutamide N~35 Combination expansion ZEN enzalutamide; Patients progressing on abiraterone N~20-25 Combination expansion ZEN enzalutamide; Patients progressing on enzalutamide N~10-15 Dose escalation near completion, Expansion cohorts enrolling Robust target modulation at well tolerated doses, prolonged dosing without dose interruption/reduction is tolerated Clinical activity in patients progressing on abiraterone/enzalutamide Significant response in primary abiraterone progressors (rpfs and PSA) >65 patients dosed to date 17

18 ZEN-3694 Development in mcrpc: Combination Study Update Abiraterone Progressors (Updated September 19, 2018) Lead-in Current SOC ZENITH s Target Extending time on therapy well beyond SOC Efficacy at well tolerated doses below MTD 18

19 Response of ZEN enzalutamide in patients progressing on enzalutamide: ZEN-3694 re-sensitizing tumors Prior Therapy Median time to radiographic progression = 10.5 mo., similar for prior abiraterone or enzalutamide therapy PR = partial response Progressing radiographically upon study entry Progressing by PSA upon study entry Progressing clinically upon study entry Expected time to radiographic progression (3-6 mo.) after PSA progression: Attard et al. 2017, PREVAIL study ** Target for ZEN enzalutamide, 32 weeks Swim lanes only shown for patients ongoing and with confirmed radiographic/clinical progression 19

20 Extensive Translational Medicine Plan Understand Responders/Non-Responders to Design Future Trials Translational program designed for molecular profiling ARi resistant patients and effect of ZEN-3694 on resistant markers, potential correlation of response to molecular signature Circulating tumor cells Enumeration, markers, and signatures Whole blood Whole blood PD marker assay for target modulation Cancer immune panel Target engagement ZEN-3694 PBMCs Peripheral blood mononuclear cells Plasma Immuno Oncology markers, Tolerance Markers, T cell receptor sequencing Exploratory markers and cytokine panel Immunohistochemistry Oncology markers Histology Tumor biopsy Primary + Metastasis RNA-sequencing Expressed mutations and profiles Pathway analysis Immuno-oncology markers 20

21 Strong Durable PSA Response with ZEN-3694+Enzalutamide in Patients with Poor Prior Response to Abiraterone PSA ug/l PSA ug/l PSA profile of 5 patients with poor prior response to Abi PSA profile of 3 patients with significant and durable PSA response PSA dose response Prior abiraterone ZEN enzalutamide Prior abiraterone ZEN enzalutamide Weeks 21

22 Artificial Intelligence Program Developed Based on Zenith s Clinical Data 22

23 Recent Zenith Publication Covers 23

24 Todays Agenda for Zenith Capital Corp. Epigenetics The Mechanism Behind Our Approach The Potential of BET Inhibition Prostate Cancer Rationale Review Promising Early Clinical Results & Case studies Next Steps for Zenith 24

25 Strong Rational for BETi/PARPi Combination in TNBC Combination of BETi/PARPi is an innovative strategy to overcome intrinsic and acquired resistance to PARP inhibition, allowing for use of PARP inhibitors across a wider spectrum of cancers and use past the initial development of resistance to PARPi Sensitize cancers with primary resistance (HR-proficient cancers) Repressed BET activity impairs BRCA1 and RAD51 expression, subsequently converting HR-proficient tumors to HR-deficient ones Re-sensitize tumors with acquired HRproficiency to treatment with PARPi BET inhibition overcomes PARPi resistance by repressing the expression of secondary BRCA1 mutations that restore BRCA1 function, or by blocking the expression of BRCA1 and RAD51 Enhance response to PARPi in tumors with HR-deficient cancer (BRCA1/2 mutated) BET inhibition further blocks RAD51 expression 25

26 ZEN-3694 Combination with a PARP Inhibitor in TNBC: Efficient POC Study Phase 1b/2: Combination with PARPi in TNBC non gbrca1/2m N~50 Objective Study design Patient Population Number of patients (N) Dose Duration Endpoints Show safety and activity of the combination in TNBC patients Phase 1b dose escalation Phase 2 Simon two step, open label non randomized TNBC: non germline BRCA1/2m, advanced metastatic, < 3 prior chemo therapy regimen, ER<10%, PR<10% and HER2-negative by IHC and/or FISH N~ 9-12 for Dose escalation Simon 2-stage design H o TNBC = 20% ORR, Target ORR = 40%, N= 17 1 st stage, N= 17 for 1 st stage, progress to second stage if number of responders > 4, N=20 for second stage, 10% alpha, 90% power ZEN-3694 starting dose: 72mg once daily 6 months for dose escalation; 12 months for expansion cohorts (assuming 10 clinical sites) Phase 1b: Safety, PK/PD, MTD, RP2D Phase 2 TNBC: ORR, DOR, PFS Exploratory: Explore biomarkers of activity and resistance 26

27 Prominent Clinical Sites and Investigators Institution Investigator Background MSKCC Mark Robson Led Olympiad study for Astra Zeneca MD Anderson Jennifer Litton Led Embraca Ph. 3 study for Pfizer University of Kansas Priyanka Sharma TNBC specialist University of Pennsylvania Susan Domcheck Breast cancer specialist Banner Health MD Anderson Cancer Center Lida Mina Breast cancer specialist Jules Bordet (Belgium) Philippe Afthimos Led Merck s and BI s BETi studies VHIO (Spain) Mafalda Olivera Involved in ER+ BETi trials for Gilead and GSK CIOCC (Spain) Valentina Boni Breast cancer specialist UZ Leuven (Belgium) Kevin Punie Breast cancer specialist 27

28 Opportunity in Immuno Oncology: Strong Rationale for Checkpoint Combinations BET bromodomain inhibition cooperates with PD-1 blockade to facilitate antitumor response in Kras-mutant non-small cell lung cancer.adeegbe DO, et al. Cancer Immunol Res

29 Summary Zenith is focused on ZEN-3694 combinations with SOC extending and expanding the value of existing therapeutics ZEN-3694 can be administered safely at doses that modulate BET targets Prostate/XTANDI combination: Promising clinical activity of ZEN Enzalutamide in ARi resistant mcrpc patients TNBC/PARPi combination: Ph. 1b/2 of ZEN PARPi in TNBC (non germline-brca1/2m) to commence soon PD-1/PD-L1 combination with ZEN-3694 has compelling pre-clinical and clinical rationale ER+ Breast Cancer: Preclinical rationale to address resistance to CDK4/6 inhibitors 29

30 Leading epigenetic company translating bromodomain biology into impactful therapies